Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.
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PMID:A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood. 211 83

The pharmacologic treatment of heart failure and low cardiac output syndrome in the cardiac surgical patient continues to be a challenge in the nursing management of these patients. While the catecholamines have been of proven inotropic benefit over the years, their inherit risks of increased myocardial oxygen consumption, tachyphylaxis and poor tolerance in many patients have lead to the search for other medications to augment cardiac performance. Amrinone, the only drug available for use in the U.S. from the class of phosphodiesterase inhibitors, acts as both an inotrope and vasodilator to increase cardiac output without an increase in myocardial oxygen consumption. This paper reviews pharmacological management of heart failure in the cardiac surgical patient and nursing considerations specific to amrinone and combination inotropic therapy management.
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PMID:Management of heart failure in cardiac surgical patients: amrinone and other pharmacologic agents. 226 43

Amrinone, a new nonadrenergic, nonglycosidic agent with combined positive inotropic and vasodilating properties, was approved recently for parenteral use in the treatment of left ventricular failure. Its mechanism of action is mediated primarily by selective phosphodiesterase fraction III inhibition, although at high doses alterations of calcium transport may occur. Acute hemodynamic changes produced by amrinone include augmentation of cardiac output and decreases in pulmonary capillary wedge pressure, right atrial pressure and systemic vascular resistance. Heart rate and blood pressure remain unaltered. Myocardial oxygen consumption declines concomitantly with the decrease in systolic wall tension. The efficacy of amrinone is comparable to that of dobutamine and dopamine. Synergistic interactions with catecholamines and vasodilators are described. Adverse effects are minimal, with dosage limited predominantly by decreases in filling pressures.
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PMID:Intravenous use of amrinone for the treatment of the failing heart. 241 Nov 22

The purpose of this study was to investigate the possible roles of selective inhibition of cyclic nucleotide phosphodiesterase (PDE) isozymes, adenylate cyclase activation, and tissue cyclic 3',5'-adenosine monophosphate (cyclic AMP) elevation in the positive inotropic action of five new cardiotonic drugs. Three PDE isozymes (PDE I, II and III), homogenates, and slices of guinea pig ventricles were used. The inotropics amrinone, milrinone, AR-L 115BS, MDL 17,043, and RMI 82,249 all inhibited cyclic AMP hydrolysis by PDE III in a concentration-dependent manner, as did the PDE inhibitors aminophylline and 1-methyl-3-isobutylxanthine (MIX). All drugs except for AR-L 115BS inhibited PDE III at concentrations lower than those producing a standard inotropic response. A significant correlation (r = 0.80, P less than 0.05) was observed between PDE III inhibition and inotropic activity for six of the drugs. Only aminophylline and MIX, but none of the cardiotonic drugs, inhibited cyclic AMP hydrolysis by PDE I and II and cyclic 3',5'-guanosine monophosphate (cyclic GMP) hydrolysis (amrinone not tested) by PDE I. Further, none of the cardiotonic drugs inhibited the calmodulin-stimulated cyclic AMP hydrolysis by PDE I, indicating their lack of calmodulin antagonist activity. These drugs also did not stimulate adenylate cyclase activity but all increased net cyclic AMP formation from ATP in guinea pig ventricular homogenates through inhibition of cyclic AMP breakdown. Amrinone, milrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, raised cyclic AMP levels significantly (P less than 0.05) in guinea pig ventricular slices. Also, amrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, potentiated forskolin-induced cyclic AMP increase. These data taken together suggest that the specific inhibition of cyclic AMP PDE III isozyme and the consequent elevation of tissue cyclic AMP levels in cardiac tissue are an important mechanism of action of amrinone, milrinone, MDL 17,043 and RMI 82,249. Because AR-L 115BS did not increase cyclic AMP levels, it is likely that another mechanism may participate in the inotropic response to AR-L 115BS.
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PMID:Effects of several newer cardiotonic drugs on cardiac cyclic AMP metabolism. 242 28

Amrinone and milrinone are new cardiotonic drugs that have potent inotropic and vasodilatory properties. The mechanism of action of these agents is controversial, but the positive inotropic component is thought to be due to the inhibition of phosphodiesterase. Because amrinone and milrinone have been shown to be involved primarily in cyclic AMP-mediated processes, we examined the effect of these agents on cyclic AMP-dependent protein kinase. The results indicate that amrinone and milrinone inhibit cyclic AMP-dependent protein kinase activity by competing with ATP but not cyclic AMP binding sites. Dissociation constants (Ki) of amrinone and milrinone for ATP binding sites on protein kinase were calculated to be 100-300 microM and 842 microM, respectively. The phosphodiesterase inhibitor isobutylmethylxanthine (1 mM) had no effect on protein kinase activity. Amrinone and milrinone inhibited the catalytic subunit of protein kinase to the same degree as the holo-enzyme by competitively inhibiting the binding of ATP. Amrinone and milrinone had no effect on phospholipid-sensitive, calcium-dependent protein kinase indicating that there may be differences in the ATP binding sites on these two protein kinases. Inhibition of cyclic AMP-dependent protein kinase by amrinone and milrinone occurs at concentrations higher than those used clinically. However, because amrinone and milrinone are lipophilic drugs, they may be useful tools for the investigation of protein kinase mediated reactions.
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PMID:Inhibition of cyclic AMP-dependent protein kinase activity by the cardiotonic drugs amrinone and milrinone. 243 Jan 62

Amrinone and trapidile belong to a group of positive inotropic and simultaneously vasodilating substances, whose effects are based on an inhibition of phosphodiesterase (PDE), thus enriching intracellular c-AMP. In neutrophilic granulocytes these PDE-antogonists will produce an inhibition of adherence and phagocytosis, whereas the migration was not affected. The lower leukocyte effective concentration of 10 mmol/l can be achieved by a therapeutical application, so that a slight inhibition of the leukocyte function has to be accounted for as a side effect.
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PMID:[Effect of amrinone and trapidil on adherence, migration and phagocytic behavior of neutrophilic granulocytes of the human]. 245 5

1. The chronotropic and inotropic effects of amrinone, carbazeran and 3-isobutyl-1-methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined. 2. Amrinone (2.4 x 10(-4)M-2 x 10(-3) M), carbazeran (9.1 x 10(-6) M-1.2 x 10(-3) M), and IBMX (1.8 x 10(-5) M-4.5 x 10(-4) M) produced concentration-dependent positive inotropic responses of papillary muscle preparations, the rank order of potency being carbazeran = IBMX greater than amrinone. Sub-threshold positive inotropic concentrations of all three compounds potentiated the positive inotropic effects of isoprenaline; leftward shifts in the concentration-effect curves were 5 fold (IBMX), 11 fold (amrinone) and 46 fold (carbazeran). 3. Amrinone and IBMX produced concentration-dependent positive chronotropic responses in isolated right atria and showed a similar rate selectivity to isoprenaline, but carbazeran elicited a decrease in beating frequency. None of these drugs potentiated the positive chronotropic effects of isoprenaline. 4. Concentrations of amrinone, carbazeran and IBMX that produced similar positive inotropic responses were associated with different increases in papillary muscle cyclic AMP and cyclic GMP concentrations. 5. All three compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition. 6. The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX. In contrast, carbazeran exerts both positive inotropic and negative chronotropic effects. Phosphodiesterase inhibition and elevation of intracellular cyclic AMP concentration may be involved, at least in part, in the cardiac effects of these drugs.
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PMID:Chronotropic and inotropic actions of amrinone, carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition. 247 44

Amrinone is a selective inhibitor of phosphodiesterase fraction 3 in both cardiac and smooth muscle. Intravenous administration in humans produces increased contractility and vasodilation of venous capacitance and arterial conductance vessels. The elimination half-life in healthy patients is reported to be 2.6 to 4.1 hours, making it the only long-acting positive inotropic agent available that can be administered either as an intravenous bolus or by infusion. A low incidence of side effects, often minor, has been reported with intravenous use. Thrombocytopenia does not seem to be a problem with short-term use. Amrinone represents a new approach in the pharmacologic therapy for ventricular dysfunction following cardiac surgery.
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PMID:Amrinone: pharmacokinetics and pharmacodynamics. 252 Oct 45

In the treatment of acute heart failure, conventional therapy with epinephrine, norepinephrine, dopamine, and dobutamine may be used effectively to treat inotropic abnormalities. However, the addition of a vasodilator to catecholamine therapy may be needed to help improve lusitropic function. Because it seems to exert positive inotropic and lusitropic effects, the phosphodiesterase inhibitor amrinone may be a valuable addition to the anesthesiologist's armamentarium for the treatment of acute heart failure. When used as adjunctive therapy with catecholamines, amrinone has been shown to exert a significant additive and synergistic effect. Amrinone may also be the inotrope of choice in patients who are refractory to therapy with conventional inotropes, due to its positive inotropic and lusitropic effects, combined with its vasodilating effects. Because of its broad pharmacodynamic spectrum, amrinone may effectively control all of the major elements involved in myocardial performance--preload, afterload, contractility, and heart rate.
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PMID:Amrinone: is it the inotrope of choice? 252 Oct 51

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.
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PMID:Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs. 259 32


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